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Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development
Ryosuke Tsunematsu1, Keiko Nakayama, Yuichi Oike
1Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
The Journal of Biological Chemistry
|December 16, 2003
Summary
Mammalian Fbw7 protein is essential for embryonic vascular development. Its deficiency impairs blood vessel formation by disrupting the Notch4-Hey1 signaling pathway, leading to embryonic lethality.
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- Mammalian Fbw7 is an F-box protein crucial for SCF ubiquitin ligase complexes.
- Fbw7 is expressed in embryonic endothelial cells, suggesting a role in vascular development.
Purpose of the Study:
- To investigate the role of Fbw7 in embryonic vascular development using a mouse knockout model.
- To elucidate the molecular mechanisms underlying Fbw7's function in angiogenesis.
Main Methods:
- Generation and analysis of Fbw7-deficient mice (Fbw7(-/-)).
- In utero embryonic lethality assessment and phenotypic analysis of vascular abnormalities.
- In vitro para-aortic splanchnopleural explant cultures.
- Analysis of Notch4 and Hey1 expression levels in Fbw7(-/-) embryos.
Main Results:
- Fbw7(-/-) embryos exhibited embryonic lethality between days 10.5-11.5 with severe vascular defects.
- Impaired vascular remodeling in the brain and yolk sac, and absence of major trunk veins were observed.
- Fbw7 deficiency led to accumulation of Notch4 and increased expression of its downstream target Hey1.
Conclusions:
- Mammalian Fbw7 is indispensable for embryonic vascular development.
- Fbw7 negatively regulates the Notch4-Hey1 pathway, which is critical for angiogenesis.
- Disruption of Fbw7 function leads to severe vascular abnormalities and embryonic lethality.